Chronic exercise training, consisting of repeated bouts of exercise over a sustained period, has undisputed effects to improve whole-body glucose homeostasis and insulin sensitivity, adaptations that are critical for people with diabetes. While these beneficial adaptations to training are well described, the underlying cellular and molecular mechanisms are not fully understood. Although the effects of exercise training have largely been investigated in the context of adaptations to skeletal muscle, there has been little investigation into the role that other tissues may play in mediating the effects of exercise training on glucose homeostasis. Preliminary data generated for this application show that transplantation of subcutaneous white adipose tissue from exercise-trained mice into sedentary recipients dramatically improves glucose tolerance, well above what occurs in adipose tissue transplanted from untrained animals. This effect is present as early as nine days post-transplantation and is associated with an increase in glucose uptake in both skeletal muscle and intrascapular brown adipose tissue, both suggesting that an adipose tissue-secreted factor may mediate the effects on glucose tolerance. The increase in glucose tolerance nine days post-transplantation is associated with an increase in glucose uptake in both skeletal muscle and intrascapular brown adipose tissue. To understand the mechanism for these beneficial effects of exercise, exercise-trained adipose tissue was studied biochemically and by microarray. Exercise training resulted in profound adaptations to subcutaneous adipose tissue, including the statistically significant alterations in >250 putative secreted proteins. Based on these findings, this project is designed to test the novel hypothesis that exercise training causes adaptations to subcutaneous adipose tissue that result in secretion of adipokines that in turn function in a paracrine or endocrine manner to improve whole body and tissue glucose homeostasis. There are three specific aims: 1) To determine if subcutaneous adipose tissue from exercise-trained mice exerts endocrine effects to enhance skeletal muscle metabolism, signaling networks, mitochondrial markers, and fiber distribution; 2) To determine the effects of transplanting subcutaneous adipose tissue from exercise-trained mice on brown adipose tissue and liver metabolism; and 3) To identify and determine the function of novel adipokines derived from the subcutaneous adipose tissue of exercise-trained mice. The use of state-of-the-art physiological and biochemical assessments will provide a powerful approach for elucidation of the physiological mechanisms underlying the important molecular effects of exercise on overall metabolic health. These studies have the potential to define novel biologics to aid in the treatment of obesity, type 2 diabetes, and other metabolic diseases.